Metabolically Stable Alkoxyalkyl Esters of Antiviral or Antiproliferative Phosphonates, Nucleoside Phosphonates and Nucleoside Phosphates

ABSTRACT

The present invention relates to phosphonate, nucleoside phosphonate or nucleoside phosphate compounds, compositions containing them, processes for obtaining them, and their use in treating a variety of medical disorders, in particular viral infections, cancers and the like.

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 11/736,614, filed Apr. 18, 2007, which claims priority to U.S.Application Ser. No. 60/746,318, filed May 3, 2006, each of which isentitled “Metabolically Stable Alkoxyalkyl Esters of Antiviral orAntiproliferative Phosphonates, Nucleoside Phosphonates and NucleosidePhosphates.” Each of these applications is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to orally administered drugs for treatmentof viral infections and certain cancers. In particular, the presentinvention relates to metabolically stable alkoxyalkyl esters ofphosphonates, nucleoside phosphonates and nucleoside phosphates,compositions containing them, processes for obtaining them, and theiruse in treating a variety of medical disorders, in particular viralinfections, cancers and the like.

BACKGROUND OF THE INVENTION

Nucleoside phosphonates have antiviral, antiproliferative and a varietyof other therapeutic benefits. Among these are the antiviral nucleosidephosphonates, such as, for example, cidofovir, cyclic cidofovir,adefovir, tenofovir, and the like, as well as the 5′-phosphonates andmethylene phosphonates of azidothymidine (AZT), ganciclovir, acyclovir,and the like. In these compounds, the 5′-hydroxyl of the sugar moiety,or its equivalent in acyclic nucleosides (ganciclovir, penciclovir,acyclovir) which do not contain a complete sugar moiety, is replacedwith a phosphorus-carbon bond. In the case of the methylenephosphonates, a methylene group replaces the 5′-hydroxyl or itsequivalent, and its carbon atom is, in turn, covalently linked to thephosphonate.

Upon cellular metabolism of nucleoside phosphonates, two additionalphosphorylations occur to form the nucleoside phosphonate diphosphatewhich represents the equivalent of nucleoside triphosphates. Antiviralnucleoside phosphonate diphosphates are selective inhibitors of viralRNA or DNA polymerases or reverse transcriptases. That is to say, theirinhibitory action on viral polymerases is much greater than their degreeof inhibition of mammalian cell DNA polymerases α, β and γ or mammalianRNA polymerases. Conversely, the antiproliferative nucleosidephosphonate diphosphates inhibit cancer cell DNA and RNA polymerases andmay show much lower selectivity versus normal cellular DNA and RNApolymerases.

As noted above, one class of antiviral and antiproliferative compoundsare the antiviral nucleoside phosphonates. Two representative structuresof this class of compounds, namely CDV and HPMPA, are set forth below:

Another class of phosphonates is the 5′-phosphonates and methylenephosphonates of azidothymidine, ganciclovir, acyclovir, and the like. Incompounds of this type, the 5′-hydroxyl of the sugar moiety, or itsequivalent in acyclic nucleosides (ganciclovir, penciclovir, acyclovir),which do not contain a complete sugar moiety, is replaced with aphosphorus-carbon bond. In the case of the methylene phosphonates, amethylene group replaces the 5′-hydroxyl or its equivalent, and itscarbon atom is, in turn, covalently linked to the phosphonate. Tworepresentative structures of this class of compounds, namely AZT5′-phosphate and AZT 5′-phosphonate, are set forth below.

Another class of therapeutically effective compounds is the nucleosidephosphates, such as, acyclovir monophosphate,2′-O-methyl-guanosine-5′-phosphate, 2′-O-methyl-cytidine-5′-phosphateand 2′-C-methyl-cytidine-5′-phosphate. Two representative structures ofthis class of compounds are set forth below:

Yet another class is the antiviral phosphonates, phosphonoformate andphosphonoacetate as illustrated below.

Various substituent groups may be attached to phosphonates andphosphates to produce derivatives having various degrees ofpharmacological potency. One class of derivative compounds are thealkoxyalkyl esters, such as hexadecyloxypropyl cidofovir (HDP-CDV),which is illustrated by the following general structure:

CDV itself is not orally active; however esterification of CDV withcertain alkoxyalkanols such as hexadecyloxypropanol dramaticallyincreases its antiviral activity and selectivity in vitro and confers adegree of oral bioavailability. The alkyl chain length of these CDVanalogs is related to solubility and the ability of the compounds toassociate with biomembranes.

Although alkoxyalkyl esters of nucleoside phosphates and phosphonates,such as hexadecyloxypropyl-cidofovir (HDP-CDV), have therapeuticallybeneficial properties, they suffer from pharmacological disadvantages asorally administered agents. Orally administered drugs are usually takenup from the small intestine into the portal vein, which exposes the drugto potentially rapid lipid metabolism in the enterocytes of the smallintestines and in the liver. Alkoxyalkyl esters of phosphates andphosphonates, such as HDP-CDV can be incorporated into cell membraneswhere the phosphate or phosphonate is subsequently liberated inside thecell or can be oxidatively metabolized by the cytochrome P450s such asCYP3A4 in the liver or intestine leading to omega oxidation of the alkylchain followed by beta oxidation. It has recently been determined thatalkoxyalkyl esters of phosphates and phosphonates can be oxidized at theterminal end of the alkyl chain by omega oxidation and are furtherdegraded by beta oxidation to short chain inactive metabolites. Thisprocess, which is illustrated in FIG. 1 for nucleoside monophosphonateHDP-CDV, may be very rapid and is deleterious to the intendedpharmacologic effect of the compounds. In the case of HDP-CDV, theinactive metabolite is water soluble, virologically inactive, andrapidly excreted in the urine. Rapid metabolism by this pathway maylower plasma levels of the prodrug, and reduce the antiviral efficacy ofHDP-CDV and alkoxyalkyl esters of phosphonates, nucleoside phosphonatesand nucleoside phosphates.

There is therefore a continuing need for more stable pharmaceuticalagents to treat a variety of disorders, such as those caused by viralinfection and inappropriate cell proliferation, e.g. cancer. Thus, it isan object of the present invention to develop chemically modifiedphosphonates, nucleoside phosphonates and nucleoside phosphates that canslow the metabolism of oral antiviral and anticancer compounds.

SUMMARY OF THE INVENTION

The present invention includes esters of phosphonates, nucleosidephosphonates and nucleoside phosphates (referred to collectivelyhereinafter as esters) that are resistant to metabolic inactivationresulting from oxidation of these compounds in the liver. Morespecifically, the present invention includes terminal or penultimatebranched chain, unsaturated and halogen substituted alkoxyalkyl estersof phosphonate compounds, wherein said substituents stabilize thesecompounds by providing metabolic stability during absorption in thesmall intestine, first pass liver metabolism and subsequent distributionto peripheral tissues. Included in the present invention are methods forusing said esters for treating various diseases and conditions.

The compounds and methods of this invention are based upon the uniqueinsight that ω-oxidation of lipid esters of phosphonates and phosphatesmay be slowed by placing a blocking group or groups at or near thepenultimate carbon of the alkyl chain. Potential blocking groupsinclude, but are not limited to alkyl groups, including, but not limitedto methyl, ethyl and propyl, cyclopropyl and halogens. Potentialblocking groups also include alkenyl groups containing one or moredouble bonds, including a terminal double bond. Although substitutedalkoxyalkyl phosphates and alkylglycerol phosphates are known in theart, the use of penultimate or terminally substituted alkyl chains tostabilize lipid phosphate or phosphonate ester drugs against rapid omegaand beta oxidation has not been reported previously. Phosphonatecompounds contemplated for use in accordance with the present inventioninclude those having antiviral and antiproliferative activity.

Representative examples of the phosphonate compounds and esters thereofcontemplated for use in accordance with the present invention are setforth in the references cited in Table 1. Also included within the scopeof the instant invention are nucleoside analogs with antiviral activityagainst hepatitis C, which can be converted to their alkoxyalkyl5′-phosphates or their alkylglycerol phosphates. Examples of nucleosidesin this class of compounds include, but are not limited to 2′-C-methyladenosine, 2′-C-methyl guanosine, 7-deaza-2′-methyl adenosine,2′-C-methyl cytosine. Other nucleosides and analogs thereof contemplatedfor use in accordance with this invention following conversion to theiralkoxyalkyl 5′-phosphates or their alkylglycerol phosphates are setforth in the references cited in Table 2.

Further included are nucleoside analogs with antiviral activity againsthepatitis B, which may be converted to their 5′-phosphates,5′-phosphonates or 5′-methylene phosphonates. Exemplary nucleosides inthis class of compounds include, but are not limited to 3TC, FTC, DAPD,L-FMAU, entecavir, telbivudine and various β-L-2′-deoxycytidine,β-L-2′-deoxyadenine and β-L-2′-deoxythymidine analogs described byBryant et al. ((January 2001) Antimicrob Agents Chemother45(1):229-235).

Anticancer agents may also be derivatized according to the method ofthis invention. Some subject compounds include but are not limited to(E)-2′-deoxy-2′-fluoromethylene-cytidine (FMdC) and1-(2-deoxy-2-fluoro-4-thio-β-D-arabinosyl)cytosine (4′-thio-FAC). Otherantiproliferative nucleosides may also become active when derivatizedaccording to the invention including, but not limited to Ara-C, Ara-G,5-fluorouridine, 5-fluoro-deoxyuridine, fludarabine, gemcitabine,decitabine or alkylglycerol phosphate or alkoxyalkyl phosphate esters oftaxol. Non-nucleoside cancer agents may be similarly derivatized withthe metabolically stable alkoxyalkyl groups of the invention including,but not limited to topotecan by phosphorylating and esterifying anavailable hydroxyl group. Etoposide may be derivatized by attachingmetabolically stable groups of the invention to the phosphate residue ofetoposide.

Phosphonate and phosphate analogs contemplated for use in accordancewith the present invention are selected to improve the bioactivity,selectivity, and/or bioavailability of the antiviral orantiproliferative compounds.

In another aspect of the present invention, there are providedpharmaceutical formulations containing the analogs of the phosphonatecompounds described herein.

In yet another aspect of the present invention, there are provided avariety of therapeutic methods, e.g. methods for treating viralinfections and methods for treating disorders caused by inappropriatecell proliferation, e.g. cancer and the like.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates schematically antiviral activation and metabolicinactivation pathways for hexadecyloxypropyl cidofovir (HDP-CDV).

FIG. 2 depicts representative structures of “Metabolism Resistant”lipophilic esters of cidofovir.

FIG. 3 depicts a graph of the % of drug remaining versus time forHDP-CDV and 15-methyl-HDP-CDV (15M-HDP-CDV). This figure illustratesthat the degradation of branched alkoxyalkyl ester derivative15M-HDP-CDV by monkey liver fractions is markedly slower than that ofthe straight chain alkoxyalkyl ester derivative HDP-CDV. The methods aredescribed in Example 13.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention includes chemical methods for synthesizingalkoxyalkyl esters having certain moieties at or near the omega end ofthe alkyl chain which block or slow degradation and metabolicinactivation. Specifically, the present invention includes terminal orpenultimate branched chain, unsaturated and halogen substituted estersof phosphonate compounds, wherein said substituents stabilize thesecompounds by providing resistance to oxidation. Phosphonates, nucleosidephosphonates and nucleoside phosphates having antiviral or anticanceractivity are subjects of the invention.

Various terms are used herein to refer to aspects of the presentinvention. To aid in the clarification of the description of thecomponents of this invention, the following definitions are provided.

It is to be noted that the term “a” or “an” entity refers to one or moreof that entity; for example, a phosphonate refers to one or morephosphonates. As such, the terms “a” or “an”, “one or more” and “atleast one” are used interchangeably herein.

It is also to be noted that in some cases for purposes of illustrationonly a single stereoisomer is depicted for a particular compound.However, the method of the invention is not limited to any particularisomer and can be extended to the S enantiomer, the R enantiomer orracemic mixtures thereof.

As used herein, the term “prodrug” refers to derivatives ofpharmaceutically active compounds that have chemically or metabolicallycleavable groups and become the pharmaceutically active compound bysolvolysis or under in vivo physiological conditions.

The term “purine or pyrimidine base” includes, but is not limited to,6-alkylpurine and N⁶-alkylpurines, N⁶-acylpurines, N⁶-benzylpurine,6-halopurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkylpurine, 6-thioalkyl purine, N²-alkylpurines, 7-deazapurines,N⁴-alkylpyrimidines, N⁴-acylpyrimidines, 4-halopyrimidines,N⁴-acetylenic pyrimidines, 4-amino and N⁴-acyl pyrimidines,4-hydroxyalkyl pyrimidines, 4-thioalkyl pyrimidines, thymine, cytosine,6-azapyrimidine, including 6-azacytosine, 2- and/or4-mercaptopyrimidine, uracil, C⁵-alkylpyrimidines, C⁵-benzylpyrimidines,C⁵-halopyrimidines, C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine,C⁵-acyl pyrimidine, C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine,C⁵-cyanopyrimidine, C⁵-nitropyrimidine, C⁵-aminopyrimidine,N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl,triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, andpyrazolopyrimidinyl. Included in this definition are ring-expanded andopen-ring cogeners of any of the aforementioned purines. Functionaloxygen and nitrogen groups on the base can be protected as necessary ordesired. Suitable protecting groups are well known to those skilled inthe art, and include trimethylsilyl, dimethylhexylsilyl,t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups,acyl groups such as acetyl and propionyl, methanesulfonyl, andp-toluenesulfonyl. Preferred bases include cytosine, 5-fluorocytosine,uracil, thymine, adenine, guanine, xanthine, 2,6-diaminopurine,6-aminopurine, 6-chloropurine and 2,6-dichloropurine.

The term “alkyl” as used herein, unless otherwise specified, refers to asaturated straight or branched hydrocarbon. The alkyl group can beoptionally substituted with one or more halogens selected from the groupconsisting of F, Cl, Br or I.

The term “alkenyl” as used herein, unless otherwise specified, refers toa partially unsaturated straight or branched hydrocarbon. The alkenylgroup can be optionally substituted with one or more halogens selectedfrom the group consisting of F, Cl, Br or I.

The term “protected” as used herein and unless otherwise defined refersto a group that is added to an oxygen, nitrogen, or phosphorus atom toprevent its further reaction or for other purposes. A wide variety ofoxygen and nitrogen protecting groups are known to those skilled in theart of organic synthesis. Suitable protecting groups are described, forexample, in Greene, et al., “Protective Groups in Organic Synthesis,”John Wiley and Sons, Second Edition, 1991, which is incorporated hereinby reference in its entirety.

The nucleoside phosphonates of the instant invention can be generallyrepresented by the following structures.

wherein

-   R is selected from the group consisting of —R₁—O—R₂, wherein R₁ is    selected from the group consisting of an optionally substituted C₁    to C₁₁ alkyl group and R₂ is selected from the group consisting of a    C₆ to C₁₇ alkyl group or a C₆ to C₁₇ alkenyl group;-   wherein-   said C₆ to C₁₇ alkyl group is substituted with one or more alkyl    groups selected from the group including, but not limited to methyl,    ethyl, propyl, or cycloalkyl, including, but not limited to    cyclopropyl and/or one or more halogens selected from the group    consisting of F, Cl, Br and I; and further wherein said C₆ to C₁₇    alkyl group includes one or more substituents at or near the    terminal position of the alkyl group, in particular at the terminal    or penultimate position; and-   wherein-   said C₆ to C₁₇ alkenyl group is optionally-substituted with an alkyl    group selected from the group including, but not limited to methyl,    ethyl, propyl, a cycloalkyl group including, but not limited to    cyclopropyl and/or one or more halogens selected from the group    consisting of F, Cl, Br and I; and further wherein the said C₆ to    C₁₇ alkenyl group contains one or more double bonds, including a    terminal double bond;-   B is selected from a purine or pyrimidine base; and-   A is a counterion selected from the group including, but not limited    to H⁺, Li⁺, Na⁺, K⁺, NH₄ ⁺, tetraalkyl ammonium and other tertiary    amine salts including but not limited to triethylamine.

In one embodiment R is selected from the group of compounds having thegeneral structure:

wherein p is selected from 1 to 11 and q is selected from 6 to 17.

In another embodiment R is selected from the group of compounds havingthe general structure:

wherein p and q are as defined above.

In yet another embodiment R is selected from the group of compoundshaving the general structure:

wherein p and q are as defined above and X is a halogen. In preferredembodiments X is F.

wherein p and q are as defined above and X is independently selectedfrom a halogen. In preferred embodiments X is F.

In specific embodiments R is selected from the group consisting of oneof the structures set forth in FIG. 2.

In one embodiment of the invention derivatized nucleoside phosphonatesare analogs of cyclic cidofovir or cidofovir which can be generallyrepresented by the following structures:

wherein R and A are as defined above.

In another embodiment of the invention the derivatized nucleosidephosphonates are analogs of9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)-adenine ((S)-HMPMA) which canbe generally represented by the following structure:

wherein R and A are as defined above.

Specific analogs of cyclic cidofovir, cidofovir and HPMPA included inthe present invention include the following compounds:3-(12-methyltridecyloxy)propyl cyclic cidofovir,3-(13-methyltetradecyloxy)propyl cyclic cidofovir,3-(14-methylpentadecyloxy)propyl cyclic cidofovir,2-(17-methyloctadecyloxy)ethyl cyclic cidofovir,3-(15-methylhexadecyloxy)propyl cyclic cidofovir,3-(15-methylhexadecyloxy)ethyl (S)-cyclic HPMPA,3-(15-methylhexadecyloxy)propyl (S)-cyclic HPMPA,2-(17-methyloctadecyloxy)ethyl-(S)-cyclic HPMPA,3-(12-methyl-tridecyloxy)propyl cidofovir,3-(13-methyl-tetradecyloxy)propyl cidofovir,3-(14-methyl-pentadecyloxy)propyl cidofovir,3-(15-methyl-hexadecyloxy)propyl cidofovir, sodium,3-(15-methyl-hexadecyloxy)propyl cidofovir, ammonium,2-(17-methyl-octadecyloxy)ethyl cidofovir,2-(15-methyl-hexadecyloxy)ethyl cidofovir, 3-(phytanyloxy)propylcidofovir, 3-(15-methylhexadceyloxy)ethyl-(S)-HPMPA and2-(17-methyloctadecyloxy)ethyl-(S)-HPMPA, 3-(hex-dec-15-enyloxy)propylcidofovir, ammonium, 3-(15-fluorohexadecyloxy)propyl cidofovir,3-(15-fluorohexadecyloxy)propyl cyclic cidofovir,3-(15-fluorohexadceyloxy)propyl-(S)-HPMPA,3-(15-fluorohexadceyloxy)propyl-(S)-cyclic HPMPA,3-(16-fluorohexadecyloxy)propyl cidofovir,3-(16-fluorohexadecyloxy)propyl cyclic cidofovir,3-(16-fluorohexadceyloxy)propyl-(S)-HPMPA,3-(16-fluorohexadceyloxy)propyl-(S)-cyclic HPMPA and11-(7,7,8,8,8-pentafluoro-octyloxy)undecyl-cidofovir, ammonium.

The nucleoside phosphates and analogs thereof of the instant inventioncan be generally represented by the following structures.

wherein R is an alkoxyalkyl group having a structure as defined aboveand B is a substituted or unsubstituted pyrimidine base or their openring congeners.

Representative examples of nucleosides in this group of compoundsinclude, but are not limited to 2′-C-methyl adenosine, 2′-C-methylguanosine, 7-deaza-2′-methyl adenosine, 2′-C-methyl cytosine. Othernucleosides and analogs thereof contemplated for use in accordance withthis invention following conversion to their alkoxyalkyl 5′-phosphatesor their alkoxyalkylglycerol phosphates are set forth in the referencescited in Table 2.

Further included are nucleoside analogs with antiviral activity againsthepatitis B, which may be converted to their 5′-phosphates,5′-phosphonates or 5′-methylene phosphonates. Exemplary nucleosides inthis class of compounds include, but are not limited to 3TC, FTC, DAPD,L-FMAU, entecavir, telbivudine and various β-L-2′-deoxycytidine,β-L-2′-deoxyadenine and β-L-2′-deoxythymidine analogs described byBryant et al. ((January 2001) Antimicrob Agents Chemother45(1):229-235). Phosphates of non-nucleoside antivirals are alsosubjects of the invention including, but not limited to, zanamivir(Relenza®).

Anticancer agents may also be derivatized according to the method ofthis invention. Some representative compounds include, but are notlimited to 2′-deoxy-2′-fluoromethylene-cytidine (FMdC) and1-(2-deoxy-2-fluoro-4-thio-β-D-arabinosyl)cytosine (4′-thio-FAC). Otherantiproliferative nucleosides may also become more metabolically stablewhen derivatized according to the invention including, but not limitedto Ara-C, Ara-G, 5-fluorouridine, 5-fluoro-deoxyuridine, fludarabine,gemcitabine, decitabine or alkylglycerol phosphate or alkoxyalkylphosphate esters of taxol. Non-nucleoside cancer agents may be similarlyderivatized with the metabolically stable alkoxyalkyl esters of theinvention including, but not limited to topotecan by coupling to anavailable hydroxyl group. Etoposide may be coupled to the metabolicallystable alkoxyalkyl esters of the invention by attachment to thephosphate residue of etoposide.

Tables 1 and 2 provide examples of compounds, which may be subjected tothe chemical steps of the invention. The references cited in theseTables are hereby incorporated by reference in their entirety.

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TABLE 2 References citing illustrative analogs of nucleosides, which canbe converted to nucleoside phosphates for use according to the method ofthis invention AUTHOR DOCUMENT ID TITLE (first named) US 2003/0050229 A1Methods and compositions for treating Sommadossi, J-P hepatitis C virusUS 2003/0060400 A1 Methods and compositions for treating LaColla, P.flaviviruses and pestiviruses US 2003/0087873 A1 Modified nucleosidesfor treatment of viral Stuyver, L. infections and abnormal cellproliferation US 2004/0063622 A1 Methods and compositions for treatingSommadossi, J-P flaviviruses and pestiviruses US 2004/0067877 A12′,3′-dideoxynucleosides for prevention or Schinazi, R. F. treatment offlaviviridae infections US 2004/0097461 A1 Methods and compositions fortreating Sommadossi, J-P. hepatitis C virus US 2004/0097462 A1 Methodsand compositions for treating Sommadossi, J-P. flaviviruses andpestiviruses US 2004/0101535 A1 Methods and compositions for treatingSommadossi, J-P. hepatitis C virus US 2004/0254141 A12′-fluoronucleosides Schinazi, R. F. US 2003/0008841 A1 Anti-HCVNucleoside Derivatives Devos, R. US 2002/0055483 A1 3′- or2′-hydroxymethyl substituted Watanabe, K. A. nucleoside derivatives fortreatment of hepatitis virus infections US 2002/0147160 A1 Nucleosidederivatives as inhibitors of Bhat, B. RNA-dependent RNA viral polymeraseU.S. Pat. No. 6,846,810 B2 Antiviral Nucleoside Derivatives Martin, J.US 2005/0009775 A1 Nucleoside compounds in HCV Howes, P. D. US2005/0009737 A1 Modified fluorinated nucleosides Clark, J. US20040266722 A1 4′-substituted nucleosides as inhibitors of Devos, R. HCVRNA replication US 2004006358 A1 Nucleoside Derivatives for TreatingRoberts, C. Hepatitis C Virus Infection US 20040110717 A1 NucleosideDerivatives as Inhibitors of Carroll, S. RNA-Dependent RNA viralPolymerase US 20040121980 A1 Antiviral Nucleoside Derivatives Martin, J.US 20040147464 A1 Nucleoside Derivatives for Treating Roberts, C.Hepatitis C Virus Infection U.S. Pat. No. 6,784,161 B2 Method for theTreatment or Prevention of Ismaili, H. Flavivirus Infections UsingNucleoside Analogues US 20040229840 A1 Nucleoside Derivatives asInhibitors of Bhat, B. RNA-Dependent RNA Viral Polymerase U.S. Pat. No.6,846,810 B2 Antiviral Nucleoside Derivatives Martin, J. US 20050049204A1 Compounds for the Treatment of Otto, M. Flaviviridae Infections US20050075309 A1 Purine Nucleoside Analogues for Treating Storer, R.Flaviviridade Including Hepatitis C US 20050090463 A1 NucleosideCompounds for Treating Viral Roberts, C. Infections US 20050101550 A1Nucleoside Compounds for Treating Viral Roberts, C. Infections US20050119200 A1 Nucleoside Derivatives for Treating Roberts, C. HepatitisC Virus Infection US 20050124532 A1 Methods and Compositions forTreating Sommadossi, J. Hepatitis C Virus U.S. Pat. No. 6,911,424 B22′-Fluoronucleosides Schinazi, R. US 20050215511 A1 Nucleoside Compoundsfor Treating Viral Roberts, C. Infections US 20050272676 Al NucleosideDerivatives as Inhibitors of Bhat, B. RNA-Dependent RNA viral PolymeraseUS 20060040890 Al Anti-Viral Nucleosides Martin, J.

Compounds of the instant invention can be administered orally in theform of tablets, capsules, solutions, emulsions or suspensions, inhaledliquid or solid particles, microencapsulated particles, as a spray,through the skin by an appliance such as a transdermal patch, orrectally, for example, in the form of suppositories. The lipophilicprodrug derivatives of the invention are particularly well suited fortransdermal absorption administration and delivery systems and may alsobe used in toothpaste. Administration can also take place parenterallyin the form of injectable solutions.

The compositions may be prepared in conventional forms, for example,capsules, tablets, aerosols, solutions, suspensions, or together withcarriers for topical applications. Pharmaceutical formulationscontaining compounds of this invention can be prepared by conventionaltechniques, e.g., as described in Remington's Pharmaceutical Sciences,1985.

The pharmaceutical carrier or diluent employed may be a conventionalsolid or liquid carrier. Examples of solid carriers are lactose,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid, or lower alkyl ethers of cellulose. Examples of liquidcarriers are syrup, peanut oil, olive oil, phospholipids, fatty acids,fatty acid amines, polyoxyethylene or water. The carrier or diluent mayinclude any sustained release material known in the art, such asglyceryl monostearate or distearate, alone or mixed with a wax.

If a solid carrier is used for oral administration, the preparation maybe tabletted or placed in a hard gelatin capsule in powder or pelletform. The amount of solid carrier will vary widely, but will usually befrom about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, or sterile injectable liquid such as an aqueous or non-aqueousliquid suspension or solution.

Tablets are prepared by mixing the active ingredient (that is, one ormore compounds of the invention), with pharmaceutically inert, inorganicor organic carrier, diluents, and/or excipients. Examples of suchexcipients which can be used for tablets are lactose, maize, starch orderivatives thereof, talc, stearic acid or salts thereof. Examples ofsuitable excipients for gelatin capsules are vegetable oils, waxes,fats, semisolid, and liquid polyols.

For nasal administration, the preparation may contain a compound of theinvention dissolved or suspended in a liquid carrier, in particular, anaqueous carrier, for aerosol application. The carrier may containsolubilizing agents such as propylene glycol, surfactants, absorptionenhancers such as lecithin or cyclodextrin, or preservatives.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or non-aqueousliquids, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use.

Suitable excipients for the preparation of solutions and syrups arewater, polyols, sucrose, invert sugar, glucose, and the like. Suitableexcipients for the preparation of injectable solutions are water,alcohols, polyols, glycerol, vegetable oils, and the like.

The pharmaceutical products can additionally contain any of a variety ofadded components, such as, for example, preservatives, solubilizers,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorings, buffers, coating agents, antioxidants, diluents, and thelike.

Optionally, the pharmaceutical compositions of the invention maycomprise a compound according to the general formula combined with oneor more compounds exhibiting a different activity, for example, anantibiotic or other pharmacologically active material. Such combinationsare within the scope of the invention.

This invention provides methods of treating disorders related to viralinfections, inappropriate cell proliferation, and the like. The methodsparticularly comprise administering to a host in need thereof atherapeutically effective amount of the prodrugs of this invention.Thus, in one aspect of the invention there are provided methods fortreating disorders caused by viral infections. Indications appropriateto such treatment include susceptible viruses including, but are notlimited to human immunodeficiency virus (HIV), influenza, herpes simplexvirus (HSV), human herpes virus 6 and 8, cytomegalovirus (CMV),hepatitis B and C virus, Epstein-Barr virus (EBV), varicella zostervirus, and diseases caused by orthopox viruses (e.g., variola major andminor, vaccinia, smallpox, cowpox, camelpox, monkeypox, and the like),ebola virus, papilloma virus, and the like, lymphomas, hematologicaldisorders such as leukemia, and the like, and cancers caused by virusessuch as cervical cancer which is caused, in most cases, by the high risksubtypes of human papilloma virus.

In yet another aspect of the invention, there are provided methods fortreating disorders caused by inappropriate cell proliferation, e.g.cancers, such as melanoma, lung cancers, pancreatic cancer, stomach,colon and rectal cancers, prostate and breast cancer, the leukemias andlymphomas, and the like. Anti-cancer compounds which can be converted totheir nucleotide phosphonates or nucleoside-5′-phosphates for use ascompounds of this invention include, but are not limited to, cytarabine(ara-C), fluorouridine, fluorodeoxyuridine (floxuridine), gemcitibine,decitabine, cladribine, fludarabine, pentostatin (2′-deoxycoformycin),6-mercaptopurine and 6-thioguanine and substituted or unsubstitutedara-adenosine (ara-A), ara-guanosine (ara-G), and ara-uridine (ara-U).Anticancer compounds of the invention may be used alone or incombination with other antimetabolites or with other classes ofanticancer drugs such as alkaloids, topoisomerase inhibitors, alkylatingagents, antitumor antibiotics, and the like.

The prodrugs of the invention can be administered orally, parenterally,topically, rectally, and through other routes, with appropriate dosageunits, as desired.

As used herein, the term “parenteral” refers to subcutaneous,intravenous, intra-arterial, intramuscular or intravitaeal injection, orinfusion techniques.

The term “topically” encompasses administration rectally and byinhalation spray, as well as the more common routes of the skin andmucous membranes of the mouth and nose and in toothpaste.

“Therapeutic” as used herein, includes treatment and/or prophylaxis.When used, therapeutic refers to humans as well as other animals.

“Pharmaceutically or therapeutically effective dose or amount” refers toa dosage level sufficient to induce a desired biological result. Thatresult may be the alleviation of the signs, symptoms or causes of adisease or any other alteration of a biological system that is desired.

A “host” or “patient” is a living subject, human or animal, into whichthe compositions described herein are administered.

With respect to disorders associated with viral infections orinappropriate cell proliferation, e.g., cancer, the “effective amount”is determined with reference to the recommended dosages of the antiviralor anticancer parent compound. The selected dosage will vary dependingon the activity of the selected compound, the route of administration,the severity of the condition being treated, and the condition and priormedical history of the patient being treated. However, it is within theskill of the art to start doses of the compound(s) at levels lower thanrequired to achieve the desired therapeutic effect and to graduallyincrease the dosage until the desired effect is achieved. If desired,the effective daily dose may be divided into multiple doses for purposesof administration, for example, two to four doses per day. It will beunderstood, however, that the specific dose level for any particularpatient will depend on a variety of factors, including the body weight,general health, diet, time, and route of administration and combinationwith other drugs, and the severity of the disease being treated.

Generally, the compounds of the present invention are dispensed in unitdosage form comprising 1% to 100% of active ingredient. The range oftherapeutic dosage is from about 0.01 to about 1,000 mg/kg/day with fromabout 0.10 mg/kg/day to 100 mg/kg/day being preferred, when administeredto patients, e.g., humans, as a drug. Actual dosage levels of activeingredients in the pharmaceutical compositions of this invention may bevaried so as to administer an amount of the active compound(s) that iseffective to achieve the desired therapeutic response for a particularpatient.

Compounds of the invention can be prepared in a variety of ways, asgenerally depicted in Schemes 3 to 7 in Examples 1-9. The generalphosphonate esterification methods described below are provided forillustrative purposes only and are not to be construed as limiting thisinvention in any manner. Indeed, several methods have been developed fordirect condensation of phosphonic acids with alcohols (see, for example,R. C. Larock, Comprehensive Organic Transformations, VCH, New York,1989, p. 966 and references cited therein). Isolation and purificationof the compounds and intermediates described in the examples can beeffected, if desired, by any suitable separation or purificationprocedure such as, for example, filtration, extraction, crystallization,flash column chromatography, thin-layer chromatography, distillation ora combination of these procedures. Specific illustrations of suitableseparation and isolation procedures are in the examples below. Otherequivalent separation and isolation procedures can of course, also beused.

Example 1 (Scheme 1) outlines a general method for the synthesis ofbranched alkoxyalkanols having the general formula:

wherein p and q are as defined above.

Example 2 (Scheme 2) outlines a general method for the synthesis ofbranched methylalkoxyalkyl esters from cyclic phosphonates. Cycliccidofovir was used in this Example for purposes of illustration, howeverthis method can be extended to the use of virtually any cyclicphosphonate of interest. The following compounds were prepared using thegeneral methods set forth in Examples 1 and 2:3-(12-methyl-tridecyloxy)propyl cidofovir,3-(13-methyl-tetradecyloxy)propyl cidofovir,3-(14-methyl-pentadecyloxy)propyl cidofovir,3-(15-methyl-hexadecyloxy)propyl cidofovir, sodium,2-(17-methyl-octadecyloxy)ethyl cidofovir,2-(15-methyl-hexadecyloxy)ethyl cidofovir,3-(15-methylhexadceyloxy)ethyl-(S)-HPMPA, and2-(17-methyloctadecyloxy)ethyl-(S)-HPMPA.

Examples 3 and 4 describe the synthesis of two specific branchedalkoxyalkyl esters, namely 3-(phytanyloxy)propyl cidofovir and15-methylhexadecyloxypropyl cidofovir (15-Me HDP-CDV), ammonium, usingslight variations of the methods described in Examples 1 and 2.

Example 5 (Scheme 4) describes a general method for the synthesis of thebranched methylalkoxyalkyl esters of the instant invention fromp-toluenesulfonyloxymethyl phosphonates. The synthesis of the branchedmethylalkoxyalkyl ester 3-(15-methyl-hexadecyloxy)propyl(S)-9-[3-trityloxy-2-(phosphonomethoxy)propyl]-N⁶-trityl-adenine, wasdescribed for purposes of illustration.

Example 6 (Scheme 5) outlines a general method for the synthesis ofalkenyloxyalkyl esters having a terminal double bond. The nucleosidephosphonate cidofovir was used for purposes of illustration resulting inthe synthesis of compound 26, hexadec-15-enyl-oxypropyl-cidofovir.

Examples 7-9 (Schemes 6-8) outline general methods for the synthesis ofvarious halogenated alkoxyalkyl esters using CDV and HPMPA for purposesof illustration. Synthesis of the following compounds are exemplified:3-(15-fluorohexadecyloxy)propyl cidofovir,3-(15-fluorohexadecyloxy)propyl cyclic cidofovir,3-(15-fluorohexadecyloxy)propyl-(S)-HPMPA,3-(15-fluorohexadecyloxy)propyl-(S)-cyclic HPMPA,3-(16-fluorohexadecyloxy)propyl cidofovir,3-(16-fluorohexadecyloxy)propyl cyclic cidofovir,3-(16-fluorohexadecyloxy)propyl-(S)-HPMPA,3-(16-fluorohexadecyloxy)propyl-(S)-cyclic HPMPA and11-(7,7,8,8,8-pentafluoro-octyloxy)undecyl cidofovir.

Examples 10-12 illustrate the antiviral activity representativepenultimate branched methyl alkoxyalkyl esters of CDV and HPMPA. Theresults are set forth in Tables 3-6. As can be seen in Tables 4 and 5penultimate branched chain analogs of (S)-HPMPA were highly activeagainst vaccinia and cowpox in vitro and penultimate branched chainalkoxyalkyl cidofovir esters were effective against ectromelia virus invitro at submicromolar EC50s. As can be seen in Table 6, the branchchain analogs of (S)-HPMPA and CDV were all fully protective againstdeath from lethal poxvirus infection at doses of 5 mg/kg/day or greater.15M-HDP-(S)-HPMPA appeared to be more active than HDP-(S)-HPMPA.

The stability of the compounds of the invention is illustrated inExample 13, the data for which is set forth in FIG. 3. FIG. 3 depicts agraph of the % of drug remaining versus time for HDP-CDV and15-methyl-HDP-CDV (15M-HDP-CDV) after incubation for various times asindicated in the presence of liver S9 preparations. This figureillustrates that the degradation of branched alkoxyalkyl esterderivative 15M-HDP-CDV by monkey liver and human liver S9 fractions ismarkedly slower than that of the straight chain alkoxyalkyl esterderivative HDP-CDV. Thus, changes in the alkyl chain to mimic thefeatures of phytanic acid (3,7,11,15-tetramethyl-hexadecanoic acid) slowω oxidation of the 16th carbon. Although, the phytantyl derivativeillustrated in Example 13 contains 4 methyl groups it is also sufficientto introduce alkyl substituents or halogens at the penultimate carbon asin the hexadecyl moiety of HDP-CDV(15-methyl-hexadexyloxypropyl-cidofovir, 15M-HDP-CDV). Alternatively,terminal fluorines, cyclopropyl, alkene groups also suffice to increasemetabolic stability as described in detail above.

Examples

The following examples are provided for illustrative purposes only andare not intended to limit the scope of the invention.

General Procedures. ¹H NMR spectra were recorded on a Varian HGspectrophotometer operating at 300 MHz and are reported in units of ppmrelative to internal tetramethylsilane at 0.00 ppm. Analtech silicagel-GF (250 micron) plates were used for thin layer chromatography(TLC). The products were visualized with UV light, phospray (Supelco;Bellefonte, Pa., USA) and charring. Flash chromatography was performedwith silica gel (E. Merck silica gel 60, 230-400 mesh) or with aCombiFlash system (Teledyne Isco, Lincoln, Nebr.). Mass spectra showingthe presence of a molecular ion were obtained using electrosprayionization (MS-ESI) in both positive and negative modes.

Example 1 Preparation of Branched alkoxyalkanols

A general method for the synthesis of branched alkoxyalkanols (6) isillustrated in Scheme 1.

Scheme 1

Compound n m p 12-methyltridecyloxypropan-l-ol 1 7 313-methyltetradecyloxypropan-l-ol 1 8 314-methylpentadecyloxypropan-l-ol 3 7 3 15-methylhexadecyloxypropan-l-ol1 10 3 17-methyloctadecyloxyethan-l-ol 3 10 215-methylhexadecyloxyethan-l-ol 1 10 2 Reagents: a) magnesium, THF; b)Li₂CuCl₄, THF; c) methanesulfonyl chloride, triethylamine, CH₂Cl₂; d)1,2-ethanediol or 1,3-propanediol, NaH, N,N-DMF

Preparation of branched methylalkanols (4). With reference to Scheme 1,branched methylalkanols were synthesized from bromoalkanols (3) andbranched methyl bromoalkanes (1). The chain elongation procedures aredescribed by Fouquet et al. (Fouquet and Sclosser (1974) Angew. Chem.Int. Ed. Engl. 13:82-83).

General procedure. A dry THF solution of alkylmagnesium bromide (2) wasprepared from branched methyl alkyl bromide (1, 94.2 mmol) and magnesium(113 mmol) in dry THF (90 mL). To a stirred and cooled solution ofbromoalkanol (3, 17.3 mmol) in dry THF (50 mL) was added the resultingGrignard reagent, followed by a solution of Li₂CuCl₄ (0.12 M in dry THF,8.0 mL, 0.96 mmol) at −78° C. under N₂ atmosphere. The resulting mixturewas allowed to warm to room temperature while stirring overnight. Afterthe reaction mixture had been quenched with saturated aq. NH₄Cl, it wasextracted with ethyl acetate. The extract was successively washed withwater, saturated NaHCO₃ and brine, dried with MgSO₄, and concentratedunder reduced pressure. The residue was purified by flash columnchromatography (10% ethyl acetate/hexanes) to provide the branchedmethylalkanols (4).

The following compounds were prepared using this general procedure.

12-methyltridecan-1-ol was prepared from 9-bromononan-1-ol and3-methylbutylbromide in 51% yield. The ¹H NMR and MS-ESI data matchedthose reported by Yuasa et al. (Yuasa and Tsuruta (2004) Flavour andFragrance Journal 19:199-204).

13-methyltetradecan-1-ol was prepared from 10-bromodecanol and3-methylbutylbromide in 62% yield. The ¹H NMR and MS-ESI data matchedthose reported by Yuasa et al. (Yuasa and Tsuruta (2004) Flavour andFragrance Journal 19:199-204).

14-methylpentadecan-1-ol was prepared from 9-bromononanol and5-methylhexylbromide in 55% yield. The ¹H NMR and MS-ESI data matchedthose reported by Yuasa et al. (Yuasa and Tsuruta (2004) Flavour andFragrance Journal 19:199-204).

15-methylhexadecan-1-ol was prepared from 12-bromo-1-dodecanol and3-methylbutylbromide. The ¹H NMR was identical to that reported byMasuda et al. ((2002) Biosci. Biotech. Biochem. 66:1531-1537).

17-methyloctadecan-1-ol was prepared from 12-bromo-1-dodecanol and5-methylhexylbromide in 44% yield. ¹H NMR δ 0.86 (6H), 1.10-1.40 (32H),3.64 (2H).

Preparation of branched alkoxyalkanols (6). With reference to Scheme 1,branched alkoxyalkanols were prepared by conversion of the branchedmethyl alkanols (4) to the corresponding methanesulfonate derivatives(5), followed by reaction with either 1,3-propanediol or 1,2-ethanediol.

General procedure for preparation of methanesulfonates. To a solution ofalkanol 4 (100 mmol) and triethylamine (15.2 g, 150 mmol) in CH₂Cl₂ (100mL) was added methanesulfonyl chloride (15 g, 130 mmol) at 0° C. Thereaction mixture was stirred overnight then poured into ice water andextracted with diethyl ether. The extract was washed with saturated aq.NaHCO₃ and brine, dried with MgSO₄ and concentrated under reducedpressure to give the branched methyl alkylmethanesulfonate 5 in 79-89%yield. The compound was employed in the next step without furtherpurification.

General procedure for preparation of alkoxyalkanols. 1,3-propanediol or1,2-ethanediol (10 mmol) was added carefully to a suspension of sodiumhydride (2 mmol) in dry N,N-DMF and stirred for 30 min. To the mixturewas then added the branched methyl alkylmethanesulfonate (5, 1 mmol) indry THF. The mixture was heated to 60° C. for 4 h, and then cooled toroom temperature. After the mixture had been added to ice water it wasextracted with ethyl acetate, washed with brine and concentrated underreduced pressure. The residue was purified by flash chromatography (20%ethyl acetate/hexanes) to give the branched methylalkoxyalkanols (6).

The following compounds were prepared using these procedures.

3-(12-methyltridecyloxy)propan-1-ol,

3-(13-methyltetradecyloxy)propan-1-ol,

3-(14-methylpentadecyloxy)propan-1-ol,

3-(15-methylhexadecyloxy)propan-1-ol ¹H NMR δ 0.86 (d, 6H), 1.15 (m,1H), 1.25 (br s, 26H), 1.60-1.46 (m, 3H), 1.83 (qt, 2H), 3.43 (t, 2H),3.61 (t, 2H), 3.78 (t, 2H). MS-ESI (m/z) 315.33 (MH)⁺

2-(15-methylhexadecyloxy)ethan-1-ol

2-(17-methyloctadecyloxy)ethan-1-ol

Example 2 Preparation of Branched methylalkoxyalkyl esters from cyclicphosphonates

Branched methylalkoxyalkyl esters were prepared from cyclic phosphonatesas shown in Scheme 2 using cyclic cidofovir for purposes ofillustration. Briefly, the cyclic phosphonates were coupled to branchedmethylalkoxyalkanols using the Mitsunobu reaction as described by Wan etal. ((2005) Antimicrobial Agents and Chemotherapy 49:656-662) to formthe cyclic diesters which were then hydrolyzed to form the branchedmethylalkoxyalkyl esters.

General procedure for preparation of cyclic diesters (illustrated bycompound L. Anhydrous cyclic cidofovir or cyclic (S)-HPMPA (10 mmol), analkoxyalkanol (6) (20 mmol) and triphenylphosphine (20 mmol) weredissolved or suspended in anhydrous N,N-dimethylformamide (15 mL) andstirred vigorously under a nitrogen atmosphere. Diisopropylazodicarboxylate (20 mmol) was added in three portions over 15 min andthen the mixture was stirred overnight at room temperature. The solventwas then evaporated under vacuum, and the residue was purified by flashcolumn chromatography (15% EtOH/CH₂Cl₂). The products were finallyrecrystallized from p-dioxane. The coupled products were equimolarmixtures of the axial and equatorial diastereomers.

The following compounds were prepared:

3-(12-methyltridecyloxy)propyl cyclic cidofovir

3-(13-methyltetradecyloxy)propyl cyclic cidofovir

3-(14-methylpentadecyloxy)propyl cyclic cidofovir

2-(17-methyloctadecyloxy)ethyl cyclic cidofovir

3-(15-methylhexadecyloxy)propyl cyclic cidofovir MS-ESI (m/z) 558.54(MH)⁺

3-(15-methylhexadecyloxy)ethyl (S)-cyclic HPMPA

3-(15-methylhexadecyloxy)propyl (S)-cyclic HPMPA MS-ESI (m/z) 582.37(MH)⁺

2-(17-methyloctadecyloxy)ethyl-(S)-cyclic HPMPA MS-ESI (m/z) 596.32(MH)⁺

General procedure for preparation of branched methylalkoxyalkyl esters(illustrated by compound 8). The branched methyl alkoxyalkyl esters ofcyclic cidofovir (7) or cyclic (S)-HPMPA were suspended in 2 M NaOH (25mL/mmol), heated to 80° C. and stirred for 1 h, during which time themixtures became clear. After hydrolysis, the solutions were cooled to25° C. and acidified with glacial acetic acid to approximately pH 5. Theresulting precipitates were collected by vacuum filtration and driedunder reduced pressure. The crude products were purified either by flashcolumn chromatography (20% MeOH/CH₂Cl₂) or recrystallized from ethanol.

The following compounds were prepared:

3-(12-methyltridecyloxy)propyl cidofovir

3-(13-methyltetradecyloxy)propyl cidofovir

3-(14-methylpentadecyloxy)propyl cidofovir

3-(15-methylhexadecyloxy)propyl cidofovir, sodium MS-ESI (m/z) 598.36(M+Na)⁺

2-(17-methyloctadecyloxy)ethyl cidofovir

2-(15-methyl-hexadecyloxy)ethyl cidofovir

3-(15-methylhexadceyloxy)ethyl (S)-HPMPA

2-(17-methyloctadecyloxy)ethyl (S)-HPMPA MS-ESI (m/z) 614.30 (MH)⁺.

Example 3 Preparation of 3-(phytanyloxy)propyl cidofovir

3-(Phytanyloxy)propyl cidofovir was prepared using slight modificationsof the general methods set forth in Examples 1 and 2 as specifically setforth below.

Preparation of phytanol. Phytol (2.0 g, 6.7 mmol) was dissolved inethanol, rhodium 5% on alumina was added and mixture was placed under H₂60 psi and shaken overnight. The reaction mixture was filtered andevaporated to give the desired compound as an oil (2.0 g, 100% yield).

Preparation of phytanylmethanesulfonate. Phytanol (2.0 g, 6.7 mmol) wasdissolved in pyridine and cooled to 0° C. Methanesulfonyl chloride (1.15g, 10 mmol) was added and the reaction mixture was stirred for 4 h,after which the mixture was added to ice water and extracted with ether.The ether layer was evaporated to provide a light brown oil (1.5 g) thatwas used in the next step without further purification.

Preparation of 3-(phytanyloxy)propan-1-ol. Sodium hydride was addedcarefully to a solution of 1,3-propanediol (7.6 g, 100 mmol) inanhydrous N,N-DMF (30 mL). Phytanylmethanesulfonate (1.5 g, 4 mmol) wasadded and the mixture was heated to 60° C. and stirred for 4 h. Thereaction mixture was then poured into ice/H₂O, extracted withdichloromethane, dried over MgSO₄ and evaporated. The residue waspurified by flash column chromatography using 20% ethyl acetate/hexanesto give 3-(phytanyloxy)propan-1-ol (1.25 g, 87% yield)

Preparation of 3-(phytanyloxy)propyl cyclic cidofovir. To a stirredmixture of triphenylphosphine, (524 mg, 2 mmol) cyclic cidofovir(anhydrous, 800 mg, 3 mmol) and phytanyloxypropanol (500 mg, 1.4 mmol)was added diisopropyl azodicarboxylate (404 mg, 2 mmol). The mixture wasthen stirred overnight at room temperature. Solids were removed byfiltration and then the filtrate was concentrated and the residuepurified by flash column chromatography. Elution with 10-15%EtOH/dichloromethane afforded the cyclic ester (660 mg, 78%)

Preparation of 3-(phytanyloxy)propyl cidofovir. Phytanyloxypropyl cycliccidofovir was hydrolyzed as described in Example 2 to provide the targetcompound.

Example 4 Preparation of 15-methylhexadecyloxypropyl cidofovir (15-MeHDP-CDV)

15-Me HDP-CDV, ammonium (16) was prepared using slight modifications ofthe general methods set forth in Examples 1 and 2 as specifically setforth below and outlined in Scheme 3.

15-Methylhexadecan-1-ol (10). Into a clean flame dried and Ar flushed500 mL RBF was added 5 g (33 mmol) of commercially available 9. To thiswas added 40 mL of anhydrous THF and 970 mg (40 mmol) of Mg turnings, apellet of I₂ was added to accelerate the reaction. The reaction mixturewas refluxed for 2 hrs. It was then cooled to room temperature andfurther to −78° C. To this was added 1.6 g (6.0 mmol) of12-bromo-1-dodecanol in 10 mL of anhydrous THF followed by addition of3.3 mL (0.33 mmol) of lithium cuprate. The resulting mixture was allowedto warm to room temperature while stirring overnight followed byquenching with saturated aq. NH₄Cl and extracted with EtOAc (3×). Thecombined EtOAc layer was then successively washed with water, saturatedaq. NaHCO₃ and brine, dried over MgSO₄ and the solvents evaporated underreduced pressure. The residue was then purified by combiflash usinghexane/EtOAc as eluent to furnish 1.07 g of the compound 10 as a whitesolid in 65-70% yield.

15-Methylhexadecyl-1-tosylate (11). 22 g (86 mmol) of 10 was dissolvedin 200 mL of dry DCM and 14 mL (100 mmol) of Et₃N was added. Thesolution was cooled to 0° C. followed by addition of 19 g (100 mmol) ofTsCl. The reaction mixture was then stirred for 6 hrs at roomtemperature and washed with saturated solution of aq. NaHCO₃, theorganic layer was then dried over MgSO₄ and the solvent was evaporatedunder reduced pressure. The crude product was then purified bycombiflash using hexane/EtOAc as eluent and recrystallized over hexanesat −20° C. overnight to provide 25 g of 11 as white crystals in 70%yield.

tert-Butyldimethyl-3-(15-methylhexadecyloxy)propoxysilane (12). Into aclean flame dried and Ar flushed 2L RBF was added 22.5 ml (105 mmol) ofcommercially available 3-tert-butyldimethylsilyloxy propanol and 200 mLof anhydrous DMF was added. The mixture was cooled to 0° C. and 5.0 g ofNaH was added slowly. After complete addition the reaction mixture wasstirred at room temperature for 30 minutes and cooled to 0° C. 27 g(65.7 mmol) of 11 was then slowly added to the reaction with vigorousstirring. After complete addition the reaction mixture was heated at 80°C. for 2 hrs at which time the TLC showed complete consumption of 11.The reaction was then cooled to room temperature and quenched withdropwise addition of saturated aq. NH₄Cl. 200 mL of water was added andthe target product was extratcted with EtOAc (3×), the combined organiclayer was successively washed with water (3×), brine (1×) and dried overMgSO₄. The solvent was evaporated under reduced pressure and the residuewas purified by combiflash using hexane/ethyl acetate as an eluent tofurnish 23 g of 12 as colorless oil in 85% yield.

3-(15-methylhexadecyloxypropan-1-ol (13). To 23g (54 mmol) of 12 wasadded 216 mL of a 1 M solution of TBAF in THF and the reaction wasstirred for 16 hrs at room temperature. The reaction mixture was thenquenched with saturated solution of aq. NH₄Cl and the THF was evaporatedunder reduced pressure. The aq. solution was then diluted with 200 mL ofwater and the target product was extracted with Et₂O (3×), the combinedorganic layer was then washed with brine (1×), dried over MgSO₄ and thesolvent was removed under reduced pressure. The crude product was thenpurified by combiflash using hexane/ethyl acetate as eluent to furnish11.5 g of compound 13 in 70% yield as yellow oil.

Methanesulfonic acid-3-(15-methylhexadecyloxy)propyl ester (14). To 11 g(35 mmol) of 13 was added 25 mL of DCM and 7.3 mL (53 mmol) of Et₃N andthe mixture was cooled to 0° C. MsCl 3.0 mL (38.5 mmol) and a catalyticamount of DMAP was then added dropwise and the reaction was stirred atroom temperature overnight. The reaction mixture was then diluted with50 mL of DCM and washed successively with saturated solution of aq.NaHCO₃ (1×), water (1×) and brine (1×), dried over MgSO₄ and the solventwas evaporated under reduced pressure. The crude product was thenpurified by combiflash using hexane/ethyl acetate as eluent to furnish13 g of product 14 in quantitative yield.

Reaction of 14 with Bz-c-CDV. 2.4 g (6.6 mmol) of Bz-c-CDV was dissolvedin 10 mL of NMP and 1.7 mL (10mmol) of DIPEA was added to it followed by13 g (33 mmol) of 14. The reaction mixture was heated to 95-100° C. for16 hrs at which time TLC showed product together with some Bz-c-CDV. Thereaction was allowed to proceed for an additional 8-9 hrs, at which timeTLC showed that the reaction had not proceeded much further. At thistime, the reaction mixture was cooled to room temperature and thesolvent was evaporated under high vacuum. The residue was purified bycombiflash using chloroform/MeOH as eluent to furnish 1.8 g of 15 asyellow oil in 42% yield.

Deprotection and hydrolysis of (15). To 1.7 g (2.56 mmol) of 15 wasadded 30 mL of concentrated NH₄OH and the sealed tube was heated at 95°C. for 2-3 hrs at which time the solution turned clear. The reactionmixture was then cooled and the TLC showed the reaction to be complete.The NH₄OH was evaporated under reduced pressure and the residue wasdissolved in 5-10 ml of hot distilled water and dried in a lyophillizerover the weekend. The yellow solids were then washed thoroughly withacetone and the residue was dried in a lyophillizer overnight to furnish1.6 g of analog 16 as a yellow solid.

Example 5 Preparation of Branched methyl esters from thep-toluenesulfonyloxymethyl phosphonates

Branched methyl esters were prepared from thep-toluenesulfonyloxymethylphosphonates 18 as illustrated in Scheme 4,using synthesis of (S)-HPMPA esters for purposes of illustration. Theprocedure is based on the method reported by Beadle et al., J. Med.Chem. 49:2010-2015, 2006.

General procedure for preparation of branched methyl alkoxyalkylp-toluenesulfonyloxymethylphosphonates 18. Diethyltoluenesulfonyloxymethylphosphonate was synthesized from diethylhydroxymethylphosphonate as described by Holý and Rosenberg, ((1982)Collect. Czech. Chem. Commun. 47:3447-3463). Bromotrimethylsilane (27 g,175 mmol) was added to a solution of diethyltoluenesulfonyloxymethylphosphonate (9.5 g, 29.5 mmol) indichloromethane (anhydrous, 150 mL). The mixture was stirred at roomtemperature under a N₂ atmosphere for 18 h. The mixture was thenconcentrated under vacuum to remove solvent and excess TMSBr, thenredissolved in dichloromethane (150 mL) and cooled to 0° C. with an icebath. N,N-DMF (0.5 mL) was added, and a solution of oxalyl chloride (22g, 175 mmol) in CH₂Cl₂ (50 mL) was added dropwise over 30 min, and thenthe solution was stirred an additional 5 h. The mixture was evaporatedto an oil, which was redissolved in Et₂O (100 mL). A solution of thebranched methyl alkoxyalkanol 6 (21.5 mmol) and pyridine (10 mL) in Et₂O(50 mL) was added, and stirring was continued for about 3 hours or untilTLC analysis (1:1 hexanes/ethyl acetate) indicated completephosphonylation of the alcohol. The reaction mixture was then added tocold saturated NaHCO₃ and vigorously stirred one hour. After hydrolysiswas complete, the organic layer was separated, dried over MgSO₄ andevaporated under vacuum to give the crude esters, which were purified byflash chromatography (15% EtOH/CH₂Cl₂).

3-(15-methyl hexadecyloxy)propyl p-toluenesulfonyloxymethylphosphonatewas prepared using this procedure, MS-ESI (m/z) 561.07 (M+Na)⁺.

General procedure for preparation of branched methyl esters from thep-toluenesulfonyloxymethylphosphonates 18 is illustrated in Scheme 4using (S)-HPMPA for purposes of illustration. Briefly,(S)-9-[3-trityloxy-2-hydroxypropyl]-N6-trityl-adenine 17 was preparedfrom adenine and (S)-trityl glycidyl ether (Daiso Co., Ltd., Japan)following the method of Webb ((1989) Nucleosides & Nucleotides8:619-624). Sodium hydride (24 mg, 1.0 mmol) was added to a stirredsolution of (S)-9-[3-trityloxy-2-hydroxypropyl]-N⁶-trityladenine (640mg, 0.62 mmol) in dry triethylamine (10 mL). After 15 min., theappropriate alkoxyalkyl toluenesulfonyloxymethylphosphonate (0.65 mmol)was added and the reaction mixture was heated to 50° C. and keptovernight. After cooling, the mixture was quenched with brine andextracted with ethyl acetate (3×15 mL). The organic extracts were driedover MgSO₄ and concentrated under vacuum to provide the fully protected(S)-HPMPA esters. The residue was purified by flash chromatography (10%EtOH/CH₂Cl₂). For purposes of illustration3-(15-methyl-hexadecyloxy)propyl(S)-9-[3-trityloxy-2-(phosphonomethoxy)propyl]-N⁶-trityl-adenine wasprepared using this general method.

Deprotection and isolation of (S)-HPMPA alkoxyalkyl esters 19. Fullyprotected (S)-HPMPA esters were suspended in 80% aqueous acetic acid (20mL/mmol) and heated to 60° C. for 1 hour, or until detritylation wascomplete as determined by TLC analysis. After cooling, the solvent wasevaporated and the products 19 were purified by flash chromatography.Elution with 30% MeOH/CH₂Cl₂ provided 3-(15-methylhexadecyloxy)propyl(S)-HPMPA, MS-ESI (m/z) 600.32 (MH)⁺ as a white solid.

Example 6 Preparation of alkenyloxyalkyl esters of acyclic nucleosidephosphonates

A general method for the synthesis of alkenyloxyalkyl esters having aterminal double bond is outlined in Scheme 5 using the nucleosidephosphonate cidofovir for purposes of illustration.

Toluene-4-sulfonic acid-5-benzyloxy-pentyl ester (21). 4.0 g (20 mmol)of commercially available 20 was dissolved in 40 mL of dry DCM. 4.2 mL(30 mmols) of Et₃N was added followed by 4.2 g (22 mmols) of TsCl andcatalytic DMAP and the reaction was stirred for 16 h. 100 mL of DCM wasthen added and the reaction mixture was washed successively withsaturated aq. NaHCO₃ (1×), water (1×) and brine (1×), dried over MgSO₄,and the solvent was evaporated under reduced pressure. The crude waspurified by combiflash using hexane/ethyl acetate as an eluent tofurnish 7.0 g of tosylate 21 in quantitative yield as colorless oil.

Toluene-4-sulfonic acid-5-tert-butyl-dimethyl-silanyloxy-pentyl ester(23). 5.0 mL (20 mmols) of commercially available 22 was dissolved in 40mL of dry DCM. 4.2 mL (30 mmols) of Et₃N was added followed by 4.2 g (22mmols) of TsCl and catalytic DMAP and the reaction was stirred for 16 h.100 mL of DCM was then added and the reaction mixture was washedsuccessively with saturated aq. NaHCO₃ (1×), water (1×) and brine (1×),dried over MgSO₄, and the solvent was evaporated under reduced pressure.The crude product was purified by combiflash using hexane/ethyl acetateas an eluent to furnish 7.4 g of target tosylate 23 in quantitativeyield as colorless oil.

Tert-butyl-hexadec-15-enyloxy-dimethylsilane (25). Into a clean flamedried and Ar flushed 500 mL RBF was added 14.2 mL (65 mmol) ofcommercially available 24. To this was added 100 mL of anhydrous THF,1.9 g (78 mmol) of Mg turnings and a pellet of I₂ to accelerate thereaction and the reaction mixture was refluxed for 2 h. It was thencooled to room temperature and further to −78° C. To this was added 7.4g (20.0 mmol) of 23 in 20 mL of anhydrous THF followed by addition of6.5 mL (0.65 mmol) of lithium cuprate. The resulting mixture was allowedto warm to room temperature while stirring overnight followed byquenching with saturated aq. NH₄Cl and extracted with EtOAc (3×). Thecombined EtOAc layer was then successively washed with water, saturatedaq. NaHCO₃ and brine, dried over MgSO₄ and the solvents evaporated underreduced pressure. The residue was then purified by combiflash usinghexane/EtOAc as eluent to furnish 6.7 g of 25 as colorless oil in 95%yield.

Hexadec-15-en-1-ol (26). To 11.0 g (31 mmol) of 25 was added 124 mL of a1 M solution of TBAF in THF and the reaction was stirred for 16 h atroom temperature. The reaction mixture was then quenched with saturatedsolution of aq. NH₄Cl and THF was evaporated under reduced pressure. Theaq. solution was then diluted with 200 mL of water and the targetproduct was extracted with Et₂O (3×), the combined organic layers werethen washed with brine (1×), dried over MgSO₄ and the solvent wasremoved under reduced pressure. The crude was then purified bycombiflash using hexane/ethyl acetate as eluent to furnish 5.7 g oftarget product 26 in 77% yield as colorless oil.

Hexadec-15-enyloxymethyl-benzene (27). Into a clean flame dried and Arflushed 500 mL RBF was added 14.2 mL (65 mmol) of commercially available24. To this mixture was added 100 mL of anhydrous THF, 1.9 g (78 mmol)of Mg turnings and a pellet of I₂ to accelerate the reaction. Thereaction mixture was refluxed for 2 h and then cooled to roomtemperature and further to −78° C. To this was added 7.0 g (20.0 mmol)of 21 in 20 mL of anhydrous THF followed by addition of 6.5 mL (0.65mmol) of lithium cuprate. The resulting mixture was allowed to warm toroom temperature while stirring overnight followed by quenching withsaturated aq. NH₄Cl and extracted with EtOAc (3×). The combined EtOAclayers were then successively washed with water, saturated aq. NaHCO₃and brine, dried over MgSO₄ and the solvents evaporated under reducedpressure. The residue was then purified by combiflash using hexane/EtOAcas eluent to furnish 6.3 g of the compound 27 as colorless oil in 95%yield.

Hexadec-15-en-1-ol (26). Into clean flame dried Ar flushed 500 mL RBFwas placed 6.3 g (19 mmol) of 27 and 100 mL of dry DCM and the mixturewas cooled to −78° C. 95 mL of BCl₃ (1.0 M solution in DCM) was thenslowly added to the above solution. After complete addition the coolingbath was removed and the reaction mixture was allowed to warm to roomtemperature. Stirring was continued for an additional 30 minutes at roomtemperature after which the reaction was cooled in an ice-water bath andquenched very cautiously!! (as it turns violent) with 100 mL of water.The organic layer was then separated and washed with water, dried overMgSO₄ and the solvents evaporated under vacuum. The crude was thenpurified with combiflash using hexane/ethylacetate as eluent to furnish4.3 g of 26 in 94% yield.

Toluene-4-sulfonic acid-3-tert-butyl-dimethyl-silanyloxy-propyl ester(29). 25.0 mL (115 mmols) of commercially available 28 was dissolved in100 mL of dry DCM and 24.2 mL (173 mmols) of Et₃N was added and themixture was cooled to 0° C. To this solution was then added 24.2 g (127mmols) of TsCl and catalytic DMAP. The reaction was stirred for 16 h.300 mL of DCM was then added and the reaction mixture was washedsuccessively with saturated aq. NaHCO₃ (1×), water (1×) and brine (1×),dried over MgSO₄, and the solvent was evaporated under reduced pressure.The crude was purified by combiflash using hexane/ethyl acetate as aneluent to furnish 34 g of target tosylate 29 in 85% yield as colorlessoil.

Tert-butyl-3-hexadec-15-enyloxy-propoxy-dimethylsilane (30). Into aclean flame dried and Ar flushed 2 L RBF was added 12 g (50 mmol) of(26) and 150 mL of anhydrous DMF was added. This solution was thencooled to 0° C. and 2.6 g (65 mmol) of NaH was added slowly. Aftercomplete addition the reaction was stirred at room temperature for 30minutes and cooled to 0° C. 34.5 g (100 mmol) of 29 was then slowlyadded to the reaction with vigorous stirring. After complete additionthe reaction mixture was heated at 80° C. for 2 h at which time TLCshowed complete consumption of 26. The reaction was then cooled to roomtemperature and quenched with dropwise addition of saturated aq. NH₄Cl.200 mL of water was added and the target product was extracted withEtOAc (3×), the combined organic layers were successively washed withwater (3×), brine (1×) and dried over MgSO₄. The solvent was evaporatedunder reduced pressure and the residue was purified by combiflash usinghexane/ethyl acetate as an eluent to furnish 13.3 g of 30 as yellow oilin 65% yield.

3-Hexadec-15-enyloxy-propanol (31). To 13.1 g (31.8 mmol) of 30 wasadded 128 mL of a 1 M solution of TBAF in THF and the reaction wasstirred for 16 h at room temperature. The reaction mixture was thenquenched with saturated solution of aq. NH₄Cl and THF was evaporatedunder reduced pressure. The aq. solution was then diluted with 200 mL ofwater and the product was extracted with Et₂O (3×), the combined organiclayers were then washed with brine (1×), dried over MgSO₄ and thesolvent was removed under reduced pressure. The crude was then purifiedby combiflash using hexane/ethyl acetate as eluent to furnish 7.1 g oftarget product 31 in 75% yield as colorless oil.

Methanesulfonic acid-3-hex-dec-15-enyloxy-propyl ester (32). To 7.1 g(23.7 mmol) of 31 was added 20 mL of DCM and 5.0 mL (36 mmol) of Et₃Nand the solution was cooled to 0° C. To this cooled solution was addeddropwise 2.0 mL (26 mmol) of MsCl and a catalytic amount of DMAP. Thereaction was stirred at room temperature overnight. The reaction mixturewas then diluted with 50 mL of DCM and washed successively withsaturated solution of aq. NaHCO₃ (1×), water (1×) and brine (1×), driedover MgSO₄ and the solvent was evaporated under reduced pressure. Thecrude product was then purified by combiflash using hexane/ethyl acetateas eluent to furnish 9 g of target product 32 in quantitative yield.

Substitution of (32) with Bz-c-CDV. 1.7 g (4.6 mmol) of Bz-c-CDV wasdissolved in 10 mL of NMP and 1.2 mL (7 mmol) of DIPEA was added to itfollowed by 9 g (23.9 mmol) of 32. The reaction was heated at 95-100° C.for 24 h at which time the TLC showed the product together with someBz-c-CDV. At this stage the reaction was allowed to proceed for anadditional 4 h, but as the TLC did not show much progress, the reactionmixture was cooled to room temperature and the solvent was evaporatedunder high vacuum. The residue was purified by combiflash usingchloroform/MeOH as eluent to furnish 1.33 g of target product 26 asyellow oil in 45% yield.

Deprotection and hydrolysis of (33). To 1.3 g (2.0 mmol) of 33 was added30 mL of concentrated NH₄OH and the sealed tube was heated at 95° C. for2-3 h at which time the solution turns clear. The reaction mixture wasthen cooled and the TLC showed the reaction to be complete. The NH₄OHwas evaporated under reduced pressure and the residue was dissolved in5-10 mL of hot water and dried in lyophilizer over the weekend. Theyellow solids were then washed thoroughly with acetone and the residuewas dried in lyophilizer for overnight to furnish 1.1 g of analog 34 asa yellow solid.

Example 7 Preparation of penultimate fluorinated alkoxyalkyl esters ofacyclic nucleoside phosphonates

A general procedure for the preparation of penultimate fluorinatedalkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated inScheme 6, below. Fluoroalkoxyalkyl esters of acyclic nucleosidephosphonates such as 3-(15-fluoro-hexadecyloxy)propyl cidofovir 42(15-F-HDP-CDV) and 3-(15-fluoro-hexadecyloxy)propyl (S)-HPMPA 43(15-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, withreference to Scheme 6, commercially available 2-bromopropanoic acid 35is reduced to the alcohol with borane:THF complex solution to provide2-bromo-1-propanol 36. Fluorination of 36 is achieved with1,1,2-trifluoro-2-chloroethyldiethylamine, a mild and safe reagent toconvert 1-hydroxy-2-halogenoalkanes into the corresponding rearrangedfluoride 37. Conversion of 37 into a Grignard reagent followed byreaction with 13-bromo-tridecanol in the presence of the catalystprovides 15-fluorohexadecanol 38. Conversion of alcohol 38 into themethanesulfonate derivative, followed by reaction with 1,3-propanediolprovides 3-(15-fluorohexadecyloxy)propan-1-ol 39. Reaction of 39 withcyclic cidofovir or cyclic (S)-HPMPA as described generally in Example 2(step a), provides the cyclic esters (40 and 41, respectively) which canthen be converted to the desired compounds (42 and 43, respectively)using the general method set forth in Example 2 (step b).

Example 8 Preparation of Terminal fluorinated alkoxyalkyl esters ofacyclic nucleoside phosphonates

A general procedure for the preparation of terminal fluorinatedalkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated inScheme 7, below. Fluoroalkoxyalkyl esters of acyclic nucleosidephosphonates such as 3-(16-fluoro-hexadecyloxy)propyl cidofovir(16-F-HDP-CDV) 49 and 3-(16-fluoro-hexadecyloxy)propyl (S)-HPMPA 50(16-F-HDP-(S)-HPMPA) can be prepared using this process. Briefly, withreference to Scheme 7, the Grignard reagent prepared from1-bromo-4-fluorobutane and magnesium is reacted with 12-bromododecanol44 to obtain 16-fluorohexadecanol 45. Reaction of 45 withmethanesulfonyl chloride followed by reaction with 1,3-propanediolprovides 16-fluorohexadecyloxy-1-propanol 46. Coupling of 46 with cycliccidofovir or cyclic (S)-HPMPA as described generally in Example 2 (stepa), provides the cyclic esters (47 and 48, respectively) which can thenbe converted to the desired compounds (49 and 50, respectively) usingthe general method set forth in Example 2 (step b).

Example 9 Preparation of Terminal pentafluorinated alkoxyalkyl esters ofacyclic nucleoside phosphonates

A general procedure for the preparation of terminal pentafluorinatedalkoxyalkyl esters of acyclic nucleoside phosphonates is illustrated inScheme 8.

Toluene-4-sulfonic acid 7, 7, 8, 8, 8-pentafluoro octyl ester (52). Intoa clean flame dried 250 mL RBF under current of N₂, was added 11.8 g(53.6 mmol) of commercially available 51 which was then dissolved in 100mL of dry DCM. To this was added 11.2 mL (80.4 mmol) of triethylamineand the flask was cooled in an ice bath. To this was slowly added 11.3g(59 mmol) of TsCl followed by 62 mg (0.50 mmol) of DMAP. The reactionmixture was stirred for 3 h after which it was diluted with 100 mL ofDCM and successively washed with saturated solution of NaHCO₃, H₂O andbrine, dried over MgSO₄, filtered and evaporated to dryness. The residuewas purified using combiflash (120 g silica column) with hexane/ethylacetate as solvents to furnish 18 g (90%) of the target product 52 ascolorless oil.

11-(7,7,8,8,8-pentafluoro-octyloxy)-undec-1-ene (54). Into a clean flamedried 1 L RBF under current of N₂, was added 100 mL of dry DMF and 20 mL(96 mmols) of commercially available 53. 2.3 g (57.6 mmol) of NaH wasadded to the reaction and the mixture was stirred for 3 h at roomtemperature. 18g (48 mmols) of 52 was dissolved in 50 mL of DMF and wasslowly added to the above reaction mixture. After complete addition thestirring was continued for 2 h at room temperature and at 80° C. for 2h. The reaction was then cooled in an ice bath and quenched with asolution of saturated aq. NH₄Cl. 300 mL of water was then added andreaction mixture was extracted with DCM (4×). The combined DCM layerswere then washed with H₂O (3×), brine (1×), dried over MgSO₄, filteredand the solvent was evaporated under vacuum. The residue was thenpurified using combiflash (120 g silica column) with hexane/ethylacetate as eluent to furnish 12.86 g (72%) of the target product 54 ascolorless oil.

11-(7,7,8,8,8-pentafluoro-octyloxy)-undecan-1-ol (55). Into a cleanflame dried 1 L RBF under current of N₂, was put 12.86g (34.48 mmol) of54. To this was added 172 mL (86.2 mmol) of 9-BBN (0.5 M in THF). Thereaction was stirred for 3 h. 23 mL of 30% H₂O₂ was then added dropwiseto the reaction mixture followed by 49 mL of 15% aq. NaOH and thereaction mixture was stirred at 85° C. for 3 h. The mixture was thencooled to room temperature and THF was evaporated and the residue wasdiluted with H₂O and extracted with EtOAc (3×). The combined organiclayer was then washed with brine (1×), dried over MgSO₄, filtered andthe solvent was evaporated under vacuum. The residue was then purifiedusing combiflash (120 g silica column) with hexane/ethyl acetate aseluent to furnish 10.15 g (76%) of compound 55 as a white solid.

Methanesulfonic acid 11- (7,7,8,8,8-pentafluoro-octyloxy)-undecyl ester(56). Into a clean flame dried 250 mL RBF under current of N₂, was added10.10 g (26 mmol) of 55. To this was added 100 mL of DCM and 5.5 mL (39mmol) of Et₃N. The reaction mixture was then cooled in an ice-water bathand 2.3 mL (29 mmol) of MsCl was added and stirred for 12 h at roomtemperature. The reaction was then diluted with 200 mL of DCM and washedsuccessively with sat. aq. NaHCO₃ (1×), H₂O (2×), brine (1×), dried overMgSO₄, filtered and the solvent evaporated under vacuum. The residue wasthen purified using combiflash (120 g silica column) with hexane/ethylacetate as eluent to furnish 10.15 g (84%) of target product 56 as awhite solid.

11-(7,7,8,8,8-pentafluoro-octyloxy)-undecyl N⁴-benzoyl-cyclic cidofovir(57). Into a clean flame dried 250 mL RBF under current of N₂, wasplaced 2.0 g (5.45 mmol) of benzoyl protected c-CDV followed by 40 mL ofdry NMP and the mixture was stirred until the solution turned clear. Tothis was then added 2.9 mL (16.35 mmol) of DIPEA and 10.15 g (21.7mmols) of 56 followed by 1.3 g (11 mmol) of NaI. The reaction mixturewas then stirred at 90° C. for 16 h. Solvents were then evaporated undervacuum and the residue was purified using combiflash (120 g silicacolumn) with CHCl₃/MeOH as eluent to furnish 1.8 g (45%) of the targetproduct 57 as a yellow solid.

11-(7,7,8,8,8-pentafluoro-octyloxy)-undecyl cidofovir, ammonium salt(58). 1.8 g (2.44 mmol) of 57 was put in a tube and 40 mL of NH₄OH wasadded and the tube was sealed. The reaction mixture was then stirred at80° C. in the sealed tube for 12 h. It was then cooled to roomtemperature after which NH₄OH was evaporated under vacuum and theresidue was dissolved in 10 mL of H₂O and lyophilized. The whitishyellow solid was then washed with acetone (6×) and filtered undersuction. The solids were then dried in high vacuum for 16 h to furnish1.46 g (91%) of the target product 58 as whitish yellow solid in theform of ammonium salt. ¹H NMR, ³¹P NMR, ¹⁹F NMR, elemental analysis andLRMS data were all consistent with the structure of the target product58.

Example 10 Evaluation of Antiviral Activity of penultimate Branchedmethyl alkoxyalkyl Analogs of cidofovir (CDV) and9-(S)-(3-hydroxy-2-phonomethoxypropyl)-adenine ((S)-HPMPA) AgainstVaccinia Virus and Cowpox Virus in Vitro

Virus pool preparation. The vaccinia virus strain, Copenhagen, andcowpox virus, strain Brighton, stock pools were obtained from JohnHuggins of the U.S. Army Medical Research Institute for InfectiousDiseases, Frederick, Md. These pools were prepared in Vero cells andwere diluted 1:50 to provide working stocks.

Plaque reduction assay for efficacy. Two days prior to use, HFF cellswere plated on six-well plates and incubated at 37° C. with 10% CO₂ and90% humidity. On the day of the assay, the drugs were made up at twicethe desired concentration in 2× minimal essential medium (MEM)containing 5% fetal bovine serum (FBS) and antibiotics and dilutedserially 1:5 in 2× MEM to provide six concentrations of drug. Theinitial starting concentration was usually 200 μM and ranged down to0.06 μM. The virus to be used was diluted in MEM containing 10% FBS to adesired concentration which would give 20 to 30 plaques per well. Themedium was then aspirated from the wells, and 0.2 mL of virus was addedto each well in triplicate, with 0.2 mL of medium being added to drugtoxicity wells. The plates were incubated for 1 h with shaking every 15min. After the incubation period, an equal amount of 1% agarose wasadded to an equal volume of each drug dilution. This gave final drugconcentrations beginning with 100 μM and ending with 0.03 μM and a finalagarose overlay concentration of 0.5%. The drug-agarose mixture wasadded to each well in 2 mL volumes, and the plates were incubated for 3days, after which the cells were stained with a 1.5% solution of neutralred. After a 5- to 6-h incubation period, the stain was aspirated andthe plaques were counted using a stereomicroscope at ×10 magnification.The MacSynergy II, version 1, computer program was used to calculate the50% effective concentration (EC₅₀). The results are set forth in Tables3 and 4.

Neutral-red uptake assay for toxicity. Twenty-four hours prior to theassay, HFF cells were plated on 96-well plates at a concentration of2.5×10⁵ per mL. After 24 h, the medium was aspirated and 125 μL of drugwas added to the first row of wells and then diluted serially 1:5 usingthe Beckman BioMek liquid-handling system. After the addition of thedrug, the plates were incubated for 7 days in a CO₂ incubator at 37° C.At that time, the medium with drug was aspirated, and 200 μl of 0.01%neutral red in phosphate-buffered saline (PBS)/well was added andincubated for 1 h. The dye was aspirated, and the cells were washed withPBS using a Nunc plate washer. After the PBS was removed, 200 μL of 50%ethanol-1% glacial acetic acid (in H₂O)/well was added. The plates wereplaced on a rotary shaker for 15 min, and the optical densities wereread at 540 nm on a Bio-tek plate reader. The results are set forth inTables 3 and 4.

TABLE 3 Activity of penultimate branched methyl alkoxyalkyl analogs ofCDV against vaccinia virus and cowpox virus in HFF cells Vaccinia CowpoxCopenhagen Brighton CC₅₀ EC₅₀ EC₅₀ Compound (μM) (μM) SI^(a) (μM) SI^(a)CDV >317 ± 0    19 ± 9.9 >17 31 ± 1.7 >10 HDP-CDV 94 0.2 470 0.2 47015M-HDP-CDV 15.2 ± 5.5   0.10 152 0.34 45 14M-PDP-CDV 18 ± 1.1 0.14 1290.13 139 13M-TDP-CDV 41 ± 2   0.13 315 0.20 205 12M-TrDP-CDV 44 ± 5.40.70 63 0.90 49 17M-ODE-CDV 15 ± 4   0.032 469 0.05 300 ^(a)SI(Selectivity Index) = CC₅₀/EC₅₀ Abbreviations: CDV, cidofovir; HDP-CDV,hexadecyloxypropyl-CDV; 17M-ODE-CDV, 17-methyl-octadecyloxyethylcidofovir; 15M-HDP-CDV, 15-methyl-hexadecyloxypropyl cidofovir;14M-PDP-CDV, 14-methyl-pentadecyloxypropyl cidofovir; 13M-TDP-CDV,13-methyl-tetradecyloxypropyl cidofovir; 12M-TrDP-CDV,12-methyl-tridecyloxypropyl cidofovir

TABLE 4 Activity of penultimate branched methyl alkoxyalkyl analogs of(S)-HPMPA against vaccinia virus and cowpox virus in HFF cells VacciniaCowpox Copenhagen Brighton CC₅₀ EC₅₀ EC₅₀ Compound (μM) (μM) SI^(a) (μM)SI^(a) CDV >317 19.4 >16 38.1 >8.3 HDP-(S)-HPMPA 31.8 0.010 3,180 0.0181767 15M-HDP-(S)- 27.5 0.012 2,292 0.052 529 HPMPA ODE-(S)-HPMPA 2.10.008 263 0.012 175 17M-ODE-(S)- 0.8 0.009 89 0.011 73 HPMPA ^(a)SI(Selectivity Index) = CC₅₀/EC₅₀ Abbreviations: CDV, cidofovir;(S)-HPMPA, 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)-adenine; HDP-,hexadecyloxypropyl; ODE-, octadecyloxypropyl; 15M-HDP-,15-methyl-hexadecyloxypropyl-; 17M-ODE-, 17-methyl-octadecyloxyethyl-

Example 11 Evaluation of Antiviral Activity of penultimate Branchedmethyl alkoxyalkyl Analogs of CDV and (S)-HPMPA Against Ectromelia Virusin Vitro

Cells and Viruses. BS-C-1 cells (ATCC CCL 26) were grown in Dulbecco'smodified Eagle's medium (DMEM) containing 10% bovine serum fetal cloneIII (Hyclone, Logan, Utah), 2 mM L-glutamine (GIBCO, Grand Island,N.Y.), 100 U/mL penicillin (GIBCO), and 100 μg/mL streptomycin (GIBCO).A plaque-purified isolate of the MOS strain of ECTV (ATCC VR-1374)designated MOS-3-P2 was propagated in an African green monkey kidneycell line, BS-C-1. Virus was purified through a sucrose cushion. Virussuspensions were serially diluted in PBS+1% sera, absorbed to monolayersfor 1 h at 37° C., and overlayed with a suspension of 1% carboxyl methylcellulose in DMEM+5% Fetal clone III. After 4 days at 37° C., virusplaques were visualized and virus inactivated by the addition to eachwell of 0.5 mL of a 0.3% crystal violet/10% formalin solution.

Plaque reduction assay. CV-1 cells were plated in wells of a 24-wellcluster plate. Each monolayer was infected with 75 plaque forming units(PFU) of indicator virus in 0.1 mL of DMEM+5% Fetal clone III for 60 minat 37° C. Media was removed by aspiration and standard virus overlaymedia containing no drug or the test drug at concentrations ranging from0.05 to 50 μM was added. The plates were incubated at 37° C. for 3-4days for ECTV and 2 days for VACV-WR, monolayers were stained, andplaques counted using a stereomicroscope. The EC₅₀ concentration foreach drug was calculated. The results are set forth in Table 5.

TABLE 5 Activity of penultimate branched methyl alkoxyalkyl analogs ofCDV and (S)-HPMPA against ectromelia infection in vitro Ectromelia VirusCompound CC₅₀ (μM) EC₅₀ (μM) SI 12M-TrDP-CDV 82 0.94 57 13M-TDP-CDV 820.40 161 14M-PDP-CDV 38 0.17 137 HDP-CDV 10 0.14 42 15M-HDP-CDV 18 0.04391 17M-ODE-CDV 7.5 0.08 54 HDE-HPMPA 2.5 0.05 50 15M-HDE-HPMPA 43 0.0123.588 Abbreviations as set forth in Tables 3 and 4

Example 12 Activity of Oral 15M-HDP-(S)-HPMPA in Lethal Ectromelia VirusInfection

In vivo drug evaluation: A/Ncr mice were injected to effect with ananesthetic cocktail (ketamine 90 mg/kg/xylazine 10 mg/kg), held at 45°C. from the vertical on a intubation platform, and inoculated with 5 μlof virus suspension in each naris for a total challenge dose of 140 PFU(˜280×LD50). Approximately 2.5 min following inoculation of virus, themice were returned to their cage. Four hours following exposure to ECTV,groups of mice were treated by gavage with 0.1 ml of sterile, distilledwater alone or water containing the test compound. This treatment wasrepeated on days 1, 2, 3, and 4 for a total of five doses. The mice wereobserved over 21 days for clinical signs of disease (morbidity) andmortality. The results are set forth in Table 6.

TABLE 6 Activity of oral HDP-(S)-HPMPA, HDP-CDV and penultimate branchedmethyl analogs against lethal ectromelia infection in vivo TreatmentDaily Dose, mg/kg Mortality MDD Vehicle control — 5/5 7.6 HDP-(S)-HPMPA2.5 5/5 9.4 HDP-(S)-HPMPA 5.0 1/5 11 HDP-(S)-HPMPA 10.0 0/5 —15M-HDP-(S)-HPMPA 2.5 3/5 14.3 15M-HDP-(S)-HPMPA 5.0 0/5 —15M-HDP-(S)-HPMPA 10.0 0/5 — HDP-CDV 2.5 2/5 13 HDP-CDV 5.0 0/5 —HDP-CDV 10.0 0/5 — 13M-TDP-CDV 2.5 4/5 9.3 13M-TDP-CDV 5.0 0/5 —13M-TDP-CDV 10.0 0/5 — 14M-PDP-CDV 2.5 1/5 14 14M-PDP-CDV 5.0 0/5 —14M-PDP-CDV 10.0 0/5 — Abbreviations: HDP, hexadexyloxypropyl; 15M-HDP,15-methyl-hexadecyloxypropyl; 13M-TDP, 13-methyl-tetradecyloxypropyl;14M-PDP, 14-methyl-pentadecyloxypropyl. Drug administered orally 4 hrsafter infection daily for 5 days. MDD, Mean day of death

Example 13 Metabolic Stability Testing with Liver S9 Fractions

Target compounds were incubated in pooled S9 liver fractions from monkeyand human liver (purchased from a commercial source) at 37° C. Thecontrol sample (immediately quenched) was used to determine the responseat time zero. The ratio between the response of the incubated samplesand time zero indicated the % parent compound remaining. Compounds weredissolved in DMSO and serially diluted with buffer to a concentrationsuitable for the assay (1 to 10 μM). A portion of a high concentrationdilution (˜500 mM) was used to determine the LC-MS/MS conditions foranalysis (ionization polarity, SRM transition, collision energy).7-ethoxycoumarin was included as a control. Negative controls (withoutS9) were included to check the stability of the test compounds atincubation conditions. All assays were performed in triplicate and the %parent compound remaining was reported. Incubations were generallyperformed in microtiter plates with a protein concentration of 3 mg/mLand a compound concentration of 1 μM. Reactions were sampled at thespecified time points and stopped by the addition of a coldacetonitrile/water solution. The quenched plates were centrifuged andsubsequently analyzed by fast gradient LC-MS/MS. The results are setforth in FIG. 3.

1. A nucleoside phosphate selected from the group of compounds havingthe following structures:

wherein R is selected from the group consisting of —R₁—O—R₂, wherein R₁is selected from the group consisting of an optionally substituted C₁ toC₁₁ alkyl group and R₂ is selected from the group consisting of a C₆ toC₁₇ alkyl group or a C₆ to C₁₇ alkenyl group; wherein said C₆ to C₁₇alkyl group is substituted with one or more alkyl groups selected fromthe group consisting of methyl, ethyl, propyl, or cycloalkyl, includingcyclopropyl and/or one or more halogens selected from the groupconsisting of F, Cl, Br and I; and further wherein said C₆ to C₁₇ alkylgroup includes one or more substituents at or near the terminal positionof the alkyl group; and wherein said C₆ to C₁₇ alkenyl group isoptionally-substituted with an alkyl group selected from the groupconsisting of methyl, ethyl, propyl, a cycloalkyl group including,cyclopropyl and/or one or more halogens selected from the groupconsisting of F, Cl, Br and I; and further wherein the said C₆ to C₁₇alkenyl group contains one or more double bonds, including a terminaldouble bond; B is selected from a purine or pyrimidine base; and A is acounterion selected from the group consisting of H⁺, Li⁺, Na⁺, K⁺, NH₄⁺, tetraalkyl ammonium and other tertiary amine salts includingtriethylamine.
 2. The phosphate of claim 1 wherein R is selected fromthe group of compounds having the following structure:

wherein p is selected from 1 to 11 and q is selected from 6 to
 17. 3.The phosphate of claim 1 wherein R is selected from the group ofcompounds having the following structure:

wherein p is selected from 1 to 11 and q is selected from 6 to
 17. 4.The phosphate of claim 1 wherein R is selected from the group ofcompounds having the following structure:

wherein p is selected from 1 to 11 and q is selected from 6 to 17 and Xis a halogen.
 5. The phosphate of claim 4 wherein X is F.
 6. Thephosphate of claim 1 wherein R is selected from the group of compoundshaving the following structure:

wherein p is selected from 1 to 11 and q is selected from 6 to 17 and Xis independently selected from a halogen.
 7. The phosphate of claim 6wherein X is F.
 8. The phosphate of claim 1 wherein R is selected fromthe group of compounds having the following structures:


9. The nucleoside phosphate of claim 1 wherein R is selected to preventor decrease metabolic degradation of the phosphonate.
 10. The nucleosidephosphate of claim 1 wherein said phosphate is selected from anantiviral or an antineoplastic agent.
 11. The nucleoside phosphate ofclaim 10, wherein said antiviral agent is a derivative of a compoundselected from the group consisting of acyclovir, ganciclovir, AZT, ddI,ddA, d4T, ddC, 3TC, FTC, 2′-C-methyl adenosine, 2′-C-methyl guanosine,7-deaza-2′-methyl adenosine, 2′-C-methyl cytosine, DAPD, L-FMAU,entecavir, telbivudine and various β-L-2′-deoxycytidine,β-L-2′-deoxyadenine and β-L-2′-deoxythymidine.
 12. The nucleosidephosphate of claim 10 wherein said antineoplastic agent is selected fromthe group consisting of 2′-deoxy-2′,2′-difluorocytidine (gemcitibine),(E)-2′-deoxy-2′-fluoromethylene-cytidine (FMdC), or1-(2-deoxy-2-fluoro-4-thio-β-D-arabinosyl)cytosine (4′-thio-FAC), Ara-C,Ara-G, 5-fluorouridine, 5-fluoro-deoxyuridine, (R)-deoxycoformycin, andfludarabine.
 13. A pharmaceutical composition comprising a nucleosidephosphate according to claim 1 and a pharmaceutically acceptablecarrier.